This proposal is being submitted under challenge area "03: Biomarker discovery and validation" with the specific topic "03-MH-101: Biomarkers in mental disorders." It will lead to the hiring or retention of three fulltime staff members. In addition to the challenge area from the American Recovery and Reinvestment Act, the current proposal is consistent with two of the four objectives of the NIMH Strategic Plan: Objective 1 (Promote Discovery in Brain and Behavioral Sciences) and Objective 3 (Develop New and Better Interventions that Incorporate the Diverse Needs and Circumstances of People with Mental Illnesses). It is increasingly clear that recent advances in the treatment of the clinical symptoms of bipolar disorder (BPD) have not improved its functional outcome, which remains disappointing. BPD is highly disabling;based on recent data from the World Health Organization, BPD is the 7th leading cause of years lost to disability for men, and the 8th leading cause for women. Studies suggest that the functional recovery for BPD is no better now, and may even be worse, than it was 30 years ago. This poor functional outcome has little to do with the mood symptoms or mood syndromes. Instead, other factors must be involved, but have yet to be identified. The overarching challenge and knowledge gap addressed by this grant is that we do not know the determinants of daily functioning in BPD. In fact, there are no evidence-based strategies for improving functioning in BPD, resulting in a therapeutic gap. An extensive literature in schizophrenia research has established that basic (non-social) cognition is a key determinant of functional outcome in schizophrenia and that social cognition acts as a mediator between basic cognition and functioning. Hence, to resolve this critical gap and understand the determinants of functioning in BPD, we need to bridge two other gaps. First, we need a much better understanding of social cognition in BPD. Second, it is critical to understand how social cognition influences daily functioning in BPD. Identifying these determinants of outcome is a necessary first step before we can start to develop effective treatments to improve functional outcome in this disorder. To accomplish the goals of this project, we assembled a group of clinical scientists with experience in recruiting and assessing BPD and schizophrenia samples and the necessary range of expertise (performance assessment in chronic mental illness, clinical trial design, electrophysiology, social neuroscience, and biostatistics). Study aims will be evaluated over 2 years in a sample of 48 euthymic BPD outpatients and 36 healthy controls. We will also include 36 clinically stable schizophrenia outpatients to evaluate the relative magnitude of any impairment in BPD. Participants will be recruited from the Mood Disorder Clinic and Schizophrenia Clinic at UCLA, and mental health clinics at the VA Greater Los Angeles Healthcare System. The goals of the project will be achieved by assessing participants on five types of measures: social cognition (performance and EEG), early visual perception, basic cognition, clinical, and functional. This project has three aims: For the first aim, we will evaluate the level and pattern of impairment relative to healthy controls of social cognition biomarkers in euthymic BPD patients using performance measures from two separate domains of social cognition (recognizing social-affective stimuli, and making high-level mental inferences) and an EEG procedure. We hypothesize that BPD patients will show clear deficits on these procedures. For the second aim, we will evaluate whether euthymic BPD patients show impairment compared with healthy controls on factors that influence social cognition, including basic cognition and early visual perception. For the third aim, we will evaluate associations within the BPD sample among social cognition, its determinants (basic cognition, early visual perception) and functioning (functional capacity and community functioning). The activities in this proposal are early, but critical, steps toward larger research goals. The disability of BPD is substantial and represents an unmet therapeutic need. The longer-term objective of this research program is to understand the mechanisms and identify the determinants of functioning in BPD so that this information can guide new pharmacological and training approaches to improve functioning in this disorder. PUBLIC HEALTH RELEVANCE: The disability of bipolar disorder is substantial and represents an unmet therapeutic need -- there are no evidence-based strategies for improving functioning in bipolar disorder. The goal of this grant is to identify important determinants of daily functioning in bipolar disorder, with a focus on social cognition. The long-term objective of this research program is to understand the mechanisms and identify the determinants of functioning in bipolar disorder and to use this information to guide new pharmacological and training approaches to improve functioning in this disorder.